Biocompatible macromolecules have many important physiological functions, such as the significant effects of hyaluronic acid in visco-supplement treatment of osteoarthritis, wound healing promotion etc. However, the biocompatible macromolecules are usually turned over very quickly in vivo or easily dissolved in the body fluid, which largely limits their uses in many medical applications. For example, the course of visco-supplement treatment of hyaluronic acid for osteoarthritis is a knee injection every week for five consecutive weeks, which is inconvenient for patients and medical workers and also increases the risk of infection. The chemical modification, cross-linking or crosslinking after modification is the effective method for biocompatible macromolecules to prolong their turn over and reduce their solubility in vivo, which significantly expands their applications in clinical medicine. For example, as for the visco-supplement treatment of osteoarthritis, the efficacy of one knee injection with the cross-linked sodium hyaluronate is equal to five knee injections with the non-cross-linked sodium hyaluronate; besides, the cross-linked hyaluronic acid has also been widely used for cosmetic purpose such as dermal fillers.
Although the application of the biocompatible macromolecules in the clinical medicine has greatly been expanded through their chemical modification and/or cross-linking, there are still conflicts between theory and practical processes. On one hand, to prolong their turn over and reduce their solubility in vivo the biocompatible macromolecules should be chemical modified/cross-linked to a certain degree. Therefore all those chemically modified and/or cross-linked biocompatible macromolecule derivatives or cross-linked materials, which is widely applied in the clinical medicine currently, have a very high or relatively high degree of modification or cross-linking, such as the highly esterified derivative (up to 100% esterification) of sodium hyaluronate (HYAFF, Fidia, Italy). On the other hand, the chemical structure of the biocompatible macromolecules is changed due to the chemical modification and/or cross-linking, which affects and reduces their physiological function and biocompatible property and even causes certain side effects. For example, the study results reported by Jacob et al. showed that MeroGel® (based on the highly modified HYAFF) caused inflammatory reaction and ossification reaction (Jacob et al., Laryngoscope 112: 37-42, 2002).
However, most of the current research has focused on improving the degree of modification and/or cross-linking to prolong turn over and reduce solubility of the biocompatible macromolecule in vivo. In our opinion, the highly modified and/or cross-linked biocompatible macromolecule cannot better meet the requirements of the clinical applications in a considerable number of cases, and may even cause such side effects as an inflammatory reaction etc. Therefore, the chemical modification and/or cross-linking of the biocompatible macromolecule must be balanced between the following two factors: reducing the degree of chemical modification and/or cross-linking as far as possible so as to maintain initial structure, physiological function and biocompatibility, and meanwhile appropriately prolonging turn over and reducing solubility in vivo through chemical modification and/or cross-linking so as to meet the requirements of the clinical applications. However, it is a technical problem to balance the chemical modification and/or cross-linking of the biocompatible macromolecule between the above two factors.
The mercapto-modification and disulfide-bond cross-linking of the biocompatible macromolecule is a new method of chemical modification and cross-linking, and has many advantages and thus many important potential uses in the clinical medicine. For example, the mercapto-modified biocompatible macromolecule derivatives have been used in chemical activity modification of various small molecular drugs and polypeptide protein drugs, etc., and the cross-linked materials prepared based on these mercapto-modified biocompatible macromolecule derivatives can be used as a cell growth matrix, a wound healing and regeneration matrix, a drug sustained-release carrier, a wound dressing, an in situ embedding cell matrix, etc. (Bernkop-Schnurch, WO2000/025823; Shu et al., Biomacromolecules, 3: 1304, 2002; Bulpitt et al., WO2002/068383; Prestwich et al., WO2004/037164; Prestwich et al., WO2005/056608; Prestwich et al., WO2008/008857; Song, WO2008/071058; Song, WO2008/083542; and Gonzalez et al., WO2009/132226). In general, it was deemed that a higher degree of mercapto-modification was needed for the preparation of the subsequent cross-linked material of the mercapto-modified biocompatible macromolecule derivative, and therefore in the above disclosed reference both the degree of mercapto-modification and/or the degree of cross-linking of the biocompatible macromolecule are very high, such as the Shu et al's report wherein 26.8%-66.8% of the groups were modified and cross-linked (Shu et al., Biomacromolecules, 3: 1304, 2002).